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Myeloproliferative NeoplasmPhase 2NCT04103645

Intra-patient Dose Escalation Study to Investigate Safety and Feasibility of Vactosertib in Treating Anemic MPN Patients

A Phase 2 study testing Vactosertib in people with Myeloproliferative Neoplasm, run by Weill Medical College of Cornell University at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

This study assesses the potential of using a TGFβ receptor inhibitor for the treatment of anemic patients with myeloproliferative neoplasms. TGFβ signaling is known to be abnormally high in patients with myeloproliferative neoplasms and it is thought that abnormal TGFβ signals cause many of the problems with blood… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Myeloproliferative Neoplasm
What is being tested?
Vactosertib
Could I receive a placebo?
No, everyone receives an active treatment
How many people
2 participants
Where
1 siteUnited States
Study dates
22 Nov 2019to 10 Jul 2024
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients who meet the WHO 2016 criteria for a Ph-neg MPN (including PV, ET, MF, MDS/MPN, MPN-U).
  • Patients with MF must have DIPSS+ Intermediate or High-risk MF (primary of post-PV/ET).
  • For patients receiving cytoreductive therapy, they should be on a stable dose of current cytoreductive therapy for at least 3 months prior to C1D1.
  • Anemia as defined by HGB < 10 g/dL, or transfusion of ≥ 2 packed red blood cell (PRBC) unit within the past 4 weeks with HGB ≤8.5g/dL.
  • Ineligible, unsuitable or refractoriness to ESA therapy defined as any of the following:
  • Serum erythropoietin (EPO) >125 U/L.
Show all 13Show fewer
  • Proven ESA unsuitability is defined by history of any of the following:
  • Loss of erythroid hematologic improvement while receiving stable or increased ESA dose; or
  • ESA-attributed toxicity that, in the treating physician's opinion, makes ESA therapy unsuitable for subject.
  • ESA refractoriness defined by lack of erythroid hematologic improvement to ESA:27
  • Less than 1.5 g/dL increase in hemoglobin after at least 6 weeks of ESA therapy; or
  • Ongoing transfusion dependence that has not been reduced by > 4U over an 8-week period compared to ESA pre-treatment 8 weeks.
  • Acceptable Cardiovascular status

Who cannot join

  • Any other serious medical condition which in the Investigator's opinion would preclude safe participation in the study.
  • Patients with history of TIA or stroke within the past 12 months are excluded.
  • Female subjects who are breastfeeding, or intend to breastfeed, during the study or in the 30 days following the last dose of study drug are excluded.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Weill Medical College of Cornell University

    New York, New York, 10021

Other trials in United States

About this study

Official title: A 2-tiered, Phase 2, Rule-based, Intra-patient Dose Escalation Study to Investigate Safety and Feasibility of Vactosertib (TEW-7197) in the Treatment of Anemic Patients With Philadelphia Chromosome-negative MPNs (Ph-neg MPNs)

This study assesses the potential of using a TGFβ receptor inhibitor for the treatment of anemic patients with myeloproliferative neoplasms. TGFβ signaling is known to be abnormally high in patients with myeloproliferative neoplasms and it is thought that abnormal TGFβ signals cause many of the problems with blood cell formation in these diseases. The study design allows all patients to receive the study drug, vactosertib. The dose of vactosertib is individualized within a pre-set range based upon its effectiveness and tolerability. A total of up to 37 patients will be treated.

Read the detailed description

This is a two-tiered multi arm Phase 2 trial of vactosertib (TEW-7197) for the treatment of anemia in Ph-neg MPNs. Both tiers use a rule-based, accelerated dose escalation scheme to efficiently assess the potential of vactosertib to safely and effectively treat anemic patients with Ph-neg MPNs. The first tier of this trial (Tier 1) is an intra-patient dose finding study in 12 patients that uses a low starting dose of vactosertib for all patients. Treatment dose is escalated according to prospectively-defined rules, and a toxicity and treatment effect algorithm during the period of 16 weeks (4 treatment cycles). If pre-established efficacy and safety endpoints are met, then Tier 1 of the study will be followed by a Tier 2 expansion study with an additional 25 patients for a period of 24 weeks (6 treatment cycles).

Vactosertib will be administered concurrently with the patient's current treatment (if any). Prior to enrollment, patients must be on a stable dose of their current therapy for 3 months prior to entering the study. Supportive care measures including packed red blood cell (PRBC) transfusions for HGB <7g/dL, or symptomatic anemia, will be permitted. Administration of erythropoiesis stimulating agents (ESAs), however, will not be permitted on the trial (patients recruited would have serum EPO >125 U/L above which the benefit of ESAs is not supported).

Being tested
Vactosertib
Keywords
Anemia
Medical subject headings
Myeloproliferative Disorders, Anemia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • VactosertibDrug

    Also called TEW-7197

    50 mg BID This drug is a TGF-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs.

  • VactosertibDrug

    Also called TEW-7197

    100 mg BID This drug is a TGF-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs.

  • VactosertibDrug

    Also called TEW-7197

    150 mg BID This drug is a TGF-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs.

  • VactosertibDrug

    Also called TEW-7197

    200 mg BID This drug is a TGF-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs.

  • VactosertibDrug

    Also called TEW-7197

    The lowest dose level of vactosertib for which no DLT was observed in Tier 1 AND The lowest dose level for which at least one of the 12 subjects enrolled on Tier 1 met Criteria for Clinical Benefit. Or, if a single dose level does not fulfil both Criterion 1 and Criterion 2, the starting dose level for Tier 2 will lowest dose from Tier 1 for which no DLT was identified.

Study groups in NCT04103645
Study groupRoleWhat they receive
Tier 1: Vactosertib 50 mg BIDExperimentalVactosertib intra-patient dose finding cohort.
Receives: Drug: Vactosertib
Tier 1: Vactosertib 100 mg BIDExperimentalNot described
Receives: Drug: Vactosertib
Tier 1: Vactosertib 150 mg BIDExperimentalNot described
Receives: Drug: Vactosertib
Tier 1: Vactosertib 200mg BIDExperimentalNot described
Receives: Drug: Vactosertib
Tier 2: VactosertibExperimentalNot described
Receives: Drug: Vactosertib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Identify the Safest, Minimally Effective Starting Dose Level for Patients on Tier 1

    The safest minimally effective dose is defined as the lowest dose level for which no dose limiting toxicity (DLT) was observed in Tier 1 AND the lowest dose level for which at least one of the 12 subjects enrolled on Tier 1 meet Criteria for Clinical Benefit

    Measured: Baseline to week 16

  2. Identify Dose Limiting Toxicities (DLTs) in Patients With MPN Enrolled on Tier 1

    Identify the incidence of dose limiting toxicity (DLT) within the first 12 weeks which are defined as:

    1. Any non-hematologic grade ≥3 toxicity except for nausea, vomiting or diarrhea lasting 3 days or less
    2. Any grade 4 neutropenia of any duration
    3. Any grade ≥3 neutropenia that has not recovered to grade ≥2 within 7 days of onset
    4. Any grade ≥3 febrile neutropenia
    5. Any grade ≥3 thrombocytopenia associated with clinically significant bleeding or requiring platelet transfusion

    Measured: Baseline to week 12

  3. Identify the Maximum Tolerated Dose (MTD) of Vactosertib in Patients With MPN Enrolled on Tier 1

    Identify the Maximum Tolerated Dose (MTD) of vactosertib defined as the highest dose which does not meet the Tier 1 stopping rule. The tier 1 stopping rule is triggered if any patient experiences a Grade 5 dose limiting toxicity within the first 12 weeks of starting vactosertib or if more than five patients experience a dose limiting toxicity at any dose within the first 12 weeks on study.

    Measured: Baseline to week 12

  4. Number of Tier 2 Patients Who Have Achieved Erythropoietic Response as Defined by the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Criteria

    Number of patients who achieve an erythropoietic response defined by:

    1. HGB increase of 1.5g/dL compared to baseline hemoglobin;
    2. Reduction in PRBC transfusion rate to ≤ 50% of pre-treatment transfusion rate; or
    3. Reduction in PRBC transfusions by ≥ 4 Units over an 8-week period.

    Measured: baseline to week 16

  5. Number of Tier 2 Patients Who Have Achieved Clinical Response in Symptoms as Defined by International Working Group (IWG) Criteria

    Number of patients who have achieved clinical response defined by a reduction in Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) total score by ≥ 50% compared to pretreatment score

    Measured: baseline to week 16

  6. Number of Tier 2 Patients Who Have Achieved Splenic Response in Symptoms as Defined by International Working Group (IWG) Criteria

    Number of patients who have achieved splenic response defined by:

    1. Non-palpable spleen when baseline spleen size was 5-10 cm below left costal margin;
    2. At least 50% reduction in spleen size when baseline spleen is > 10 cm below left costal margin
    3. At least 35% reduction in spleen size as assessed by US, CT or MRI.

    Measured: baseline to week 16

  7. Identify Dose Limiting Toxicities (DLTs) in Patients With MPN Enrolled on Tier 2

    Identify the number of dose limiting toxicities (DLT) within the first 12 weeks which are defined as:

    1. Any non-hematologic grade ≥3 toxicity except for nausea, vomiting or diarrhea lasting 3 days or less
    2. Any grade 4 neutropenia of any duration
    3. Any grade ≥3 neutropenia that has not recovered to grade ≥2 within 7 days of onset
    4. Any grade ≥3 febrile neutropenia
    5. Any grade ≥3 thrombocytopenia associated with clinically significant bleeding or requiring platelet transfusion

    Measured: baseline to week 12

  8. Identify the Maximum Tolerated Dose (MTD) of Vactosertib in Patients With MPN Enrolled on Tier 2

    Identify the Maximum Tolerated Dose (MTD) of vactosertib defined as the highest dose which does not meet the Tier 2 stopping rule. The tier 2 stopping rule is triggered if any patient experiences a Grade 5 dose limiting toxicity within the first 12 weeks of starting vactosertib or if more than five patients experience a dose limiting toxicity at any dose within the first 12 weeks on study.

    Measured: baseline to week 12

Secondary outcomes (6)

  1. Number of Patients in Which a Histological Response is Seen

    Histological response is defined by reduction of any amount in grade of bone marrow fibrosis by histopathologic assessment at 16 weeks.

    Measured: 16 weeks

  2. Number of Patients in Which a Molecular Response is Seen

    Number of patients in which a molecular response is seen. Molecular response is defined by a decrease in VAF of MPN-driver mutations (eg. JAK2, CALR, and MPL allelic ratio) in blood and/or bone marrow cells

    Measured: 16 weeks

  3. Number of Patients in Which a Pharmacodynamic Response is Seen

    A pharmacodynamic response is defined as any of the following:

    1. Reduced immunohistochemical staining for SMAD2/3 phosphorylation in bone marrow biopsy sections.
    2. Reduced mean fluorescence intensity of SMAD2/3 phosphorylation staining in peripheral blood hematopoietic stem and progenitor cells (HSPCs) or mature progeny as assessed by flow cytometry.
    3. Reduced mean fluorescence intensity of SMAD2/3 phosphorylation staining in bone marrow hematopoietic stem and progenitor cells (HSPCs) or mature progeny as assessed by flow cytometry.

    Measured: 16 weeks

  4. Number of Patients Who Have Experienced Any of the Following: Hematologic Toxicities, Infections, Disease Progression, and Thrombosis Events

    Measured: baseline to 16 weeks

  5. Overall Survival Defined as the Amount of Time a Patient is Alive After Starting Study Treatment

    The overall survival range describes the average length of time subjects were followed for survival

    Measured: Week 1 Day 1 to 6 months post treatment discontinuation. This collection period for both subjects on study was over an average duration of 54 weeks.

  6. Progression Free Survival Defined as the Duration of Time From Start of Treatment to Time of Progression

    Measured: Week 1 Day 1 to 6 months post treatment discontinuation

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted25 Sep 2019
  2. Study start22 Nov 2019
  3. Primary completion10 Jul 2024
  4. Study completion10 Jul 2024

Why it stopped: Low accrual

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Model description
This is an intra-patient dose finding study which starts with low dose of vactosertib.
Masking
None (open label)
Enrolment
2 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04103645
Sponsor's protocol ID
19-06020285
Status last verified
Jun 2025
First submitted
18 Sep 2019
Last updated
2 Jul 2025
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Hernandez-Boluda JC, Correa JG, Garcia-Delgado R, Martinez-Lopez J, Alvarez-Larran A, Fox ML, Garcia-Gutierrez V, Perez-Encinas M, Ferrer-Marin F, Mata-Vazquez MI, Raya JM, Estrada N, Garcia S, Kerguelen A, Duran MA, Albors M, Cervantes F. Predictive factors for anemia response to erythropoiesis-stimulating agents in myelofibrosis. Eur J Haematol. 2017 Apr;98(4):407-414. doi: 10.1111/ejh.12846. Epub 2017 Jan 19.

    PubMed 28009442

  • Tefferi A, Cervantes F, Mesa R, Passamonti F, Verstovsek S, Vannucchi AM, Gotlib J, Dupriez B, Pardanani A, Harrison C, Hoffman R, Gisslinger H, Kroger N, Thiele J, Barbui T, Barosi G. Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report. Blood. 2013 Aug 22;122(8):1395-8. doi: 10.1182/blood-2013-03-488098. Epub 2013 Jul 9.

    PubMed 23838352

  • Barosi G, Mesa R, Finazzi G, Harrison C, Kiladjian JJ, Lengfelder E, McMullin MF, Passamonti F, Vannucchi AM, Besses C, Gisslinger H, Samuelsson J, Verstovsek S, Hoffman R, Pardanani A, Cervantes F, Tefferi A, Barbui T. Revised response criteria for polycythemia vera and essential thrombocythemia: an ELN and IWG-MRT consensus project. Blood. 2013 Jun 6;121(23):4778-81. doi: 10.1182/blood-2013-01-478891. Epub 2013 Apr 16.

    PubMed 23591792

  • Tefferi A, Guglielmelli P, Larson DR, Finke C, Wassie EA, Pieri L, Gangat N, Fjerza R, Belachew AA, Lasho TL, Ketterling RP, Hanson CA, Rambaldi A, Finazzi G, Thiele J, Barbui T, Pardanani A, Vannucchi AM. Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis. Blood. 2014 Oct 16;124(16):2507-13; quiz 2615. doi: 10.1182/blood-2014-05-579136. Epub 2014 Jul 18.

    PubMed 25037629

  • Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, Catalano JV, Deininger MW, Miller CB, Silver RT, Talpaz M, Winton EF, Harvey JH Jr, Arcasoy MO, Hexner EO, Lyons RM, Raza A, Vaddi K, Sun W, Peng W, Sandor V, Kantarjian H; COMFORT-I investigators. Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I. Haematologica. 2015 Apr;100(4):479-88. doi: 10.3324/haematol.2014.115840. Epub 2015 Jan 23.

    PubMed 25616577

  • Newberry KJ, Patel K, Masarova L, Luthra R, Manshouri T, Jabbour E, Bose P, Daver N, Cortes J, Kantarjian H, Verstovsek S. Clonal evolution and outcomes in myelofibrosis after ruxolitinib discontinuation. Blood. 2017 Aug 31;130(9):1125-1131. doi: 10.1182/blood-2017-05-783225. Epub 2017 Jul 3.

    PubMed 28674026

  • Vannucchi AM, Guglielmelli P. Traffic lights for ruxolitinib. Blood. 2017 Aug 31;130(9):1075-1077. doi: 10.1182/blood-2017-07-795880. No abstract available.

    PubMed 28860323

  • Huang J, Tefferi A. Erythropoiesis stimulating agents have limited therapeutic activity in transfusion-dependent patients with primary myelofibrosis regardless of serum erythropoietin level. Eur J Haematol. 2009 Aug;83(2):154-5. doi: 10.1111/j.1600-0609.2009.01266.x. Epub 2009 Apr 10. No abstract available.

    PubMed 19366369

  • Akel S, Petrow-Sadowski C, Laughlin MJ, Ruscetti FW. Neutralization of autocrine transforming growth factor-beta in human cord blood CD34(+)CD38(-)Lin(-) cells promotes stem-cell-factor-mediated erythropoietin-independent early erythroid progenitor development and reduces terminal differentiation. Stem Cells. 2003;21(5):557-67. doi: 10.1634/stemcells.21-5-557.

    PubMed 12968110

  • Soderberg SS, Karlsson G, Karlsson S. Complex and context dependent regulation of hematopoiesis by TGF-beta superfamily signaling. Ann N Y Acad Sci. 2009 Sep;1176:55-69. doi: 10.1111/j.1749-6632.2009.04569.x.

    PubMed 19796233

  • Scandura JM, Boccuni P, Massague J, Nimer SD. Transforming growth factor beta-induced cell cycle arrest of human hematopoietic cells requires p57KIP2 up-regulation. Proc Natl Acad Sci U S A. 2004 Oct 19;101(42):15231-6. doi: 10.1073/pnas.0406771101. Epub 2004 Oct 11.

    PubMed 15477587

  • Brenet F, Kermani P, Spektor R, Rafii S, Scandura JM. TGFbeta restores hematopoietic homeostasis after myelosuppressive chemotherapy. J Exp Med. 2013 Mar 11;210(3):623-39. doi: 10.1084/jem.20121610. Epub 2013 Feb 25.

    PubMed 23440043

  • Chabanon A, Desterke C, Rodenburger E, Clay D, Guerton B, Boutin L, Bennaceur-Griscelli A, Pierre-Louis O, Uzan G, Abecassis L, Bourgeade MF, Lataillade JJ, Le Bousse-Kerdiles MC. A cross-talk between stromal cell-derived factor-1 and transforming growth factor-beta controls the quiescence/cycling switch of CD34(+) progenitors through FoxO3 and mammalian target of rapamycin. Stem Cells. 2008 Dec;26(12):3150-61. doi: 10.1634/stemcells.2008-0219. Epub 2008 Aug 28.

    PubMed 18757300

  • Zermati Y, Fichelson S, Valensi F, Freyssinier JM, Rouyer-Fessard P, Cramer E, Guichard J, Varet B, Hermine O. Transforming growth factor inhibits erythropoiesis by blocking proliferation and accelerating differentiation of erythroid progenitors. Exp Hematol. 2000 Aug;28(8):885-94. doi: 10.1016/s0301-472x(00)00488-4.

    PubMed 10989189

  • Zhou L, Nguyen AN, Sohal D, Ying Ma J, Pahanish P, Gundabolu K, Hayman J, Chubak A, Mo Y, Bhagat TD, Das B, Kapoun AM, Navas TA, Parmar S, Kambhampati S, Pellagatti A, Braunchweig I, Zhang Y, Wickrema A, Medicherla S, Boultwood J, Platanias LC, Higgins LS, List AF, Bitzer M, Verma A. Inhibition of the TGF-beta receptor I kinase promotes hematopoiesis in MDS. Blood. 2008 Oct 15;112(8):3434-43. doi: 10.1182/blood-2008-02-139824. Epub 2008 May 12.

    PubMed 18474728

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Vactosertib in people with Myeloproliferative Neoplasm, run by Weill Medical College of Cornell University at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 2 Jul 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 2 Jul 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Identify the Safest, Minimally Effective Starting Dose Level for Patients on Tier 1 (time frame: Baseline to week 16). The study lists 8 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04103645, which also lists 34 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Jul 2025.

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